pregnancy outcomes in women with pre-existing thyroid

HAL Id: inserm-03082995https://www.hal.inserm.fr/inserm-03082995

Submitted on 18 Dec 2020

HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.

Pregnancy outcomes in women with preexisting thyroiddiseases: a French cohort study

Marion Lecorguillé, Juliane Léger, Anne Forhan, Marie Cheminat,Marie-Noëlle Dufourg, Barbara Heude, Marie-Aline Charles

To cite this version:Marion Lecorguillé, Juliane Léger, Anne Forhan, Marie Cheminat, Marie-Noëlle Dufourg, et al..Pregnancy outcomes in women with preexisting thyroid diseases: a French cohort study. Jour-nal of Developmental Origins of Health and Disease, Cambridge University Press, 2020, pp.1-10.�10.1017/S2040174420001051�. �inserm-03082995�

https://www.hal.inserm.fr/inserm-03082995

https://hal.archives-ouvertes.fr

Pregnancy outcomes in women with pre-existing thyroid diseases:

a French cohort study

Short title: Pre-pregnancy thyroid diseases

Marion Lecorguillé1, Juliane Léger

2,3,4, Anne Forhan

1, Marie Cheminat

5, Marie-Noëlle

Dufourg5

, Barbara Heude1*

, Marie-Aline Charles1,5*

1 Université de Paris, CRESS, INSERM, INRAE, F-75004 Paris, France

2National Institute of Health and Medical Research (INSERM), UMR INSERM

NeuroDiderot, DHU Protect, F-75019 Paris, France. 3Paris University, F-75019 Paris, France.

4Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Pediatric

Endocrinology Diabetology Department, Reference Center for Growth and Development

Endocrine Diseases, F-75019 Paris, France. 5Ined-Inserm-EFS joint Unit ELFE, Paris, France

Corresponding Author’s: Marion Lecorguillé, PhD student: [email protected]

Marion Lecorguillé, INSERM-CRESS U1153, Equipe 6 EARoH 16 avenue Paul Vaillant-

Couturier 94807 Villejuif Cedex

* MA Charles and B Heude contributed equally to this work.

mailto:[email protected]

Pre-pregnancy thyroid diseases

2

Abstract

Women with thyroid diseases at the beginning of pregnancy may have suboptimal thyroid

hormone levels because of potential difficulties in compensating for the physiological thyroid

hormone changes occurring in pregnancy. Our objective was to study the association between

pre-existing thyroid diseases, pregnancy complications and neonatal anthropometry.

In total, 16,395 women from the ELFE French longitudinal birth cohort were included, and

273 declared pre-pregnancy thyroid diseases. Associations were investigated with

multivariable regression models, with adjustment for relevant potential confounders. Body

mass index (BMI) was additionally adjusted for in a second stage.

As compared with other women, women with pre-pregnancy thyroid diseases were more

frequently obese (19.6% vs 9.8%) and had greater odds of gestational diabetes development

(OR = 1.58 [95% CI 1.08,2.30]) or had undergone treatment for infertility (OR = 1.57 [95%

CI 1.07,2.31]). After adjustment for BMI, the association with gestational diabetes was no

longer significant (OR = 1.27 [95% CI 0.86,1.88]). After excluding women with another

medical history, those with pre-pregnancy thyroid diseases had increased odds of premature

rupture of membranes (OR =1.51 [95% CI 1.01,2.25]). Children born from mothers with

hypothyroidism before conception due to a disease or as a potential side effect of treatment

had a smaller head circumference at birth than other children (β= -0.23 [95% CI -0.44,-0.01]

cm).

In conclusion, pre-pregnancy thyroid diseases were associated with risk of infertility

treatment, gestational diabetes, and premature rupture of membranes. The association between

history of hypothyroidism and moderate adverse effects on fetal head circumference growth

needs replication.


3

Keywords: medical history, thyroid diseases, hypothyroidism, pregnancy complications

Introduction

Several physiological changes occur during pregnancy that could affect thyroid function.

Adequate maternal thyroid function is especially important in early pregnancy and is crucial

for the development of many organs, including the fetal brain 1. During the first trimester of

gestation, thyroid hormones from the mother are the only source for the developing embryo

because fetal thyroid production begins at 12 to 14 amenorrhea weeks 2. Maternal thyroid

hormones circulate in fetal blood until birth 1–3

. Maternal thyroid hormone production

increases by 20% to 50% to maintain a euthyroid state 4. For women with pre-pregnancy

hypothyroidism, levothyroxine treatment frequently needs to be increased during pregnancy

and there is potential for periods of non-optimal treatment 4,5

.

The prevalence of thyroid disorders in pregnancy was evaluated in a recent meta-

analysis according to diagnostic criteria and screening time. Among studies using the 2.5–

97.5 percentile as a normal range for thyroid-stimulating hormone, prevalence rates were

0.5% for overt hypothyroidism, 3.5% for subclinical hypothyroidism and, in the first

trimester, 0.9% for overt hyperthyroidism and 2.2% for subclinical hyperthyroidism 6. These

pathologies must be recognized because they may be associated with pregnancy

complications and fetal development 1,4,7

.

In several studies, overt and subclinical hypothyroidism have been associated with

adverse outcomes, including miscarriage, haemorrhage, premature rupture of membranes,

gestational hypertension, diabetes, prematurity, caesarean section, induced labor and reduced

fertility 4,5,8–14

. The neonatal complications are risk of intrauterine growth retardation and low

or large birthweight 4,9,15

. The adverse effects of subclinical hypothyroidism on pregnancy


4

outcomes are still not clear, and most of these complications are related to overt

hypothyroidism and chronic autoimmune thyroiditis 16

. Maternal hyperthyroidism has been

associated with increased risk of infertility, premature birth, gestational hypertension and pre-

eclampsia, placenta abruption and induced labor, intrauterine growth retardation and fetal

hyperthyroidism 4,9,14,17–20

. The associations between thyroid autoantibodies and miscarriage

and preterm birth are also well established 4,21,22

.

However, few studies have evaluated the risk of complications during pregnancy

related specifically to pre-pregnancy thyroid diseases 23–25

. In women with pre-pregnancy

thyroid diseases, pregnancy may lead to suboptimal thyroid hormone concentration because

of the inability of the thyroid gland to adapt to physiological changes at the beginning of

pregnancy due to the disease itself or to its treatment 9. Women with a history of

thyroidectomy, radioactive iodine treatment, goiter or hypothyroidism, or Graves’ disease

need appropriate medical management of thyroid function during pregnancy 4. Thyroid

diseases are heterogenous. However, whatever the disorder, these diseases were known before

pregnancy and should have been treated before or adequately managed during pregnancy.

Thus, our aim was to explore whether or not, as a group, women with pre-pregnancy

thyroid disease had similar pregnancy outcomes as women without such a history. Taking

advantage of the data for the French national birth cohort ELFE (Etude Longitudinale

Française depuis l’Enfance), we described pregnancy and fetal outcomes in women with and

without known pre-pregnancy thyroid diseases.

Methods

Study design

The present analysis relies on data from the ELFE study, the first French national longitudinal

birth cohort. The rationale and design of the ELFE cohort were previously described in detail


5

26. Briefly, participation in the cohort was proposed to women giving birth in 349 maternity

hospitals randomly selected among the 544 public and private maternity hospitals in

metropolitan France. Recruitment took place on 25 selected days during 2011. The ELFE

cohort inclusion criteria were birth at ≥ 33 amenorrhea weeks, single or twin infants, mother ≥

18 years old, giving informed consent and not having plans to leave metropolitan France

within 3 years. Among eligible mothers, 51% agreed to participate.

The ELFE study was approved by the ethics committee of Créteil (CPP), the national

committee on information concerning health research (CCTIRS) and the Data Protection

Authority (Commission Nationale de l’Informatique et des Libertés [CNIL]).

Data collection

Research assistants collected information after birth from maternal medical records and

during a face-to-face interview while the mother was in the maternity ward.


Research assistants collected the diagnosis of severe maternal pre-pregnancy diseases or

disability (excluding history of chronic or gestational diabetes or hypertension for which

dedicated questions were asked) from medical files where such information is recorded as part

of the routine medical history assessment.

From these data, we extracted all diseases potentially associated with thyroid dysfunction. All

diseases were coded according to International Classification of Diseases, 10th

Revision. In

total, 273 women presented thyroid diseases before pregnancy; we classified these women

into three groups: women with 1) hypothyroidism due to a disease or as a potential side effect

of treatment (Hashimoto’s disease, hypothyroidism unspecified, no thyroid, thyroidectomy,

thyroid cancer and women with levothyroxine treatment; n=196), 2) hyperthyroidism

(Grave’s disease, hyperthyroidism unspecified; n=49) and 3) other thyroid diseases (goiter,


6

nodules, thyroid dysfunction or thyroid diseases unspecified, n=28). We combined women

with thyroidectomy (n=16) and thyroid cancer (n=4) in the first group because of the small

number of cases.

Pregnancy and fetal outcomes

Among all the data related to pregnancy complications, we selected for analyses the following

outcomes with a minimum prevalence of 7% in the population, which ensured a power of

90% to detect a minimal relative risk of 1.75 for these diseases with alpha 5% (power

increases for more prevalent outcomes): premature rupture of membranes (12 hr before labor

onset), gestational diabetes, induction of labor (spontaneous labor, induction of labor, elective

caesarean section), maternal hospitalization and mode of delivery (spontaneous vaginal

delivery, assisted vaginal delivery [forceps, vacuum, spatula], caesarean section). Gestational

hypertension and premature birth (< 37 amenorrhea weeks) were not studied because of too

few cases in the exposed group. We also studied treatment for infertility before pregnancy.

Birth weight, birth length, head circumference and gestational age at birth were treated as

continuous variables. Sex and gestational age-specific z scores customized for maternal

weight, height and parity were computed using a method adapted for the French 2010 national

perinatal survey, from that proposed by Gardosi 27

. Percentiles were then derived and used to

define fetal growth categories: small for gestational age (SGA, <10th

percentile), appropriate

for gestational age (AGA, 10th

to 90th

percentile) and large for gestational age (LGA, >90th

percentile).

Other maternal variables

Sociodemographic data included maternal age (continuous), parity, education level (tertiary

education as reference vs primary and secondary), professional status (employed or student,


7

housewife or parental leave, and other, including unemployment), living with a partner (yes

vs no), place of birth (born in France vs other country), and maternity unit level.

Health-related variables included state health insurance coverage (regular or specific

to precarious situations), smoking during pregnancy (yes vs no), number of prenatal

consultations (< 7, 7–9, ≥ 9), ultrasounds (≤ 5, > 5) and maternal pre-pregnancy weight and

height. Body mass index (BMI) was calculated as weight (kg) divided by the height² (m²) and

divided into 4 categories according to World Health Organization thresholds: underweight,

<18.5 kg/m²; normal weight, 18.5 to <25 kg/m²; overweight, 25.0 to <30 kg/m²; and obesity,

≥ 30 kg/m².

Population selected for analysis

In total, 55 included mothers withdrew from the ELFE cohort and asked for data deletion.

Mothers of twins (n=287) or with missing medical records (n=175) or face-to-face maternal

questionnaires (n=59) were excluded. For women with available medical records, we

excluded 1070 with missing data on medical history. Figure 1 displays the flow chart for the

population selection process. We grouped the selected women into two categories: 16,122

women with no medical history of thyroid diseases and 273 with pre-pregnancy thyroid

diseases as described above.

Statistical analysis

Descriptive analysis

We compared sociodemographic characteristics and pregnancy outcomes between patients

with and without pre-pregnancy thyroid diseases by chi-square test for categorical variables

and ANOVA for continuous variables.


8

Multivariable analysis

Multivariable logistic, linear and polytomic regression analyses were used to investigate the

association between thyroid diseases and pregnancy outcomes, estimating odds ratios (ORs)

and 95% confidence intervals (CIs). We first adjusted our analyses for potential confounders,

namely parity, smoking during pregnancy, maternal age, and maternal education. For birth

head circumference, weight and length, we additionally adjusted for gestational age and sex.

Second, we adjusted for pre-pregnancy BMI as a continuous variable and investigated its

potential role as an intermediate factor in the observed associations. We also introduced an

interaction term between pre-pregnancy BMI and pre-pregnancy thyroid diseases to test

whether the effect of a history of thyroid disease differed by maternal pre-pregnancy BMI.

Sensitivity analysis

To examine whether the observed relations were due to the thyroid diseases themselves and

not other pre-pregnancy diseases, which could be more frequent in our affected group, we

repeated our main analysis after excluding women with other medical histories such as

autoimmune diseases, history of diabetes, hypertension, and other diseases known to affect

pregnancy outcomes.

Because different types of thyroid disorders may be related to specific risks, we separately

analysed data for women with pre-pregnancy thyroid diseases associated with hypothyroidism

(as defined in the Data collection section) as compared with women without pre-pregnancy

thyroid diseases. Women with other thyroid diseases (hyperthyroidism or unspecified) were

too few to be considered in a separate analysis and were excluded from this analysis.


9

Results

Population characteristics

The characteristics of the women are summarized in Table 1. Women with pre-pregnancy

thyroid diseases were older, had a higher level of education, were twice as frequently obese,

and less often smoked during pregnancy than women without pre-pregnancy thyroid diseases.

The two groups were similar in employment status, country of birth or personal health

insurance and number of prenatal consultations, but women with pre-pregnancy thyroid

diseases had more ultrasounds during pregnancy. Women with pre-pregnancy thyroid diseases

more frequently underwent treatment for infertility and had gestational diabetes than women

without thyroid diseases (12% vs 7%, p<0.01, for both) (Table S1).

Multivariable analysis

After adjustment for the first set of confounders, the occurrence of pre-pregnancy thyroid

diseases was associated with a 1.6-fold increased risk of infertility treatment and gestational

diabetes (95% CI 1.07,2.31) and (95% CI 1.08,2.30) (Table 2) but was not associated with

mode of delivery, induction of labour, birth weight or length or head circumference. After

additional adjustment for BMI, the risk of gestational diabetes was no longer significant (OR

=1.27 [95% CI 0.86,1.88]). The interaction between BMI and pre-pregnancy thyroid diseases

was not significant for any of the pregnancy outcomes considered (p > 0.05, data not shown).

Exclusion of other medical history

We excluded women with a history of diseases other than thyroid diseases from the thyroid

diseases group (n=62) and control group (n=1995), which left 211 and 14,127 women in each

group (Table 3). Risk of premature rupture of membranes was increased for women with pre-


10

pregnancy thyroid diseases (OR = 1.51 [95% CI 1.01,2.25]) (p =0.04). The occurrence of pre-

pregnancy thyroid diseases was no longer associated with infertility or gestational diabetes.

Restriction to cases of hypothyroidism

We restricted the analysis to the comparison of women with hypothyroidism before

pregnancy (n=196) to women without thyroid diseases before pregnancy. On univariate

analysis, infertility treatment, gestational diabetes and premature rupture of membranes were

significantly more frequent for women in the hypothyroidism group (p < 0.05; Table 4). In

total, 20.4% of the women in this group were overweight and 20.9% were obese at conception

as compared with 17.2% and 9.8% of women without thyroid diseases before pregnancy.

After adjustment on educational level, parity, maternal age and smoking, the risks remained

significantly increased for the same pregnancy complications (data not shown). After an

additional adjustment for BMI, associations with premature rupture of membranes and

infertility treatment (both p=0.05) remained, but the association with gestational diabetes was

decreased (p=0.4) (Table 4). Mother’s hypothyroidism before pregnancy was associated with

reduced infant head circumference at birth (β= -0.20 [95% CI -0.39,-0.01] cm, p=0.04). After

excluding women with a history of diseases other than thyroid diseases, 149 women were in

the pre-pregnancy hypothyroidism group and 14,127 the comparison group. Mother’s

hypothyroidism was associated with increased risk of premature rupture of membranes and

slightly reduced infant head circumference at birth (β= -0.23 [95% CI -0.44,-0.01], p = 0.04)

cm (Table 5).

Discussion

Our study showed an increased risk of infertility treatment and gestational diabetes and

greater frequency of obesity for women with than without pre-pregnancy thyroid diseases.


11

After excluding women with other medical conditions known to interfere with pregnancy, the

risk of premature rupture of membranes was increased. Finally, when we specifically

investigated women with hypothyroidism before pregnancy, due to a disease or as a potential

side effect of treatment, their offspring had a smaller head circumference at birth, on average.

Our findings are consistent with the consequences of thyroid dysfunction.

Hypothyroidism, either primary or secondary to treatment of thyroid or pituitary diseases, is

often associated with excess weight 28

. Indeed 19.6% versus 9.8% of our women with and

without pre-pregnancy thyroid diseases were obese. In addition, thyroid function may be more

often screened in obese patients. Obesity is associated with insulin resistance,

hyperinsulinemia and risk of developing gestational diabetes 29

. It can explain the increased

risk of gestational diabetes in our women with pre-pregnancy thyroid diseases because the OR

decreased from 1.58 (adjusted model 1) to 1.27 after adjustment for BMI at the beginning of

pregnancy. Thyroid hormones are also essential for energy homeostasis, and a dysfunction

could affect metabolism: blood pressure, and high-density lipoprotein cholesterol,

triglycerides and glucose levels. Thyroid diseases have been found associated with increased

blood glucose levels, insulin resistance, and reduced insulin clearance 30

.

Reduced fertility is also a well-known consequence of obesity 29

, but adjustment for

BMI did not modify the risk of infertility treatment associated with pre-pregnancy thyroid

diseases. Conversely, excluding women with other diseases reduced the risk in our study,

which indicates that some of these diseases, such as autoimmune, hypothalamic or pituitary

anomalies, contribute to the risk of infertility. Care for infertility includes screening for

thyroid dysfunction and increases the probability of a diagnosis of thyroid disease before

pregnancy. Thus, reverse causality is another potential explanation for our observed

association between pre-pregnancy thyroid disease and infertility. In some studies,

autoimmune thyroiditis with the presence of anti-thyroid peroxidase antibodies have been


12

found associated with decreased fertility and miscarriage 16

. Thyroid dysfunction by itself has

also been found to affect the physiology of reproduction, miscarriage and ovulation disorders

12.

An association with premature rupture of membranes was described in several studies

of women with subclinical hypothyroidism 11,31

or positive antibodies 13

. The

pathophysiological mechanisms underlying theses associations are unclear but may include a

direct effect of thyroid antibodies by an antibody-mediated cytotoxic effect 22

, a subtle thyroid

dysfunction and/or a more generalized autoimmune dysfunction 16,22

. However, in our study,

the association between pre-pregnancy thyroid diseases and premature rupture of membranes

remained after excluding women with other medical conditions including autoimmune

diseases.

We found no association of pre-pregnancy thyroid diseases with gestational age of

birth, induction of labour or caesarean delivery, in contrast to other studies comparing women

with manifest thyroid dysfunction and other women 5,8,9,13,14

. In our study, women with pre-

pregnancy thyroid diseases should have been monitored for thyroid hormone concentrations

and we expected more subtle abnormalities than for diseases discovered during pregnancy.

Contrary to previous studies 10,15

, we did not find any association of pre-pregnancy

thyroid diseases with infant birthweight. Women with the more severe fetal outcomes may

have been less likely to participate in the study. However, we did not expect such severe cases

in relation with pre-pregnancy thyroid disease. Nevertheless, offspring of mothers with pre-

pregnancy hypothyroidism had slightly smaller head circumference at birth than those of

women without pre-pregnancy thyroid diseases after adjustment for maternal BMI (Table 5).

A few studies have published results on birth head circumference. Overt and subclinical

hypothyroidism disease have been associated with abnormal fetal growth and a decrease in

head circumference 32,33

. However, other results reported null associations with head


13

circumference 34

. The relation between maternal thyroid dysfunction and neuroimaging

outcomes for offspring has been investigated. One study showed an inverted U-shaped

association between free thyroxine maternal concentration and total gray-matter volume and

cortex volume in children 35

. Small head circumference is known to increase the risk of

subnormal neurodevelopment, 36

and long-term follow-up of the neurodevelopment of these

children is warranted. Isolated hypothyroxinaemia (decreased free thyroxine and normal

thyroid-stimulating hormone levels) is predominantly associated with adverse

neurobehavioral development in children 7, risk of poor verbal and non-verbal cognitive

development in children at 18 and 30 months 37

and delayed psychomotor development at 1

and 2 years 38

. Another recent study highlighted the importance of adequate maternal iodine

status in the early stages of pregnancy for optimal development of verbal IQ 39

.

Strengths and limitations

The strengths of our study are its nationwide scope and the availability of data from medical

records. However, the medical history information still depends on the accuracy of the

physician interview and the memory of the women, and its presence in the maternity medical

record depends on the women’s access to health care. A history of thyroid disease was indeed

more frequently reported by women with increased level of education, and missing

information in the medical history was more frequent for women in disadvantaged situations.

The lack of information on thyroid function and treatment is another limitation. There

was no attempt to search for laboratory or imaging exams or related treatments that could

confirm the diagnosis and provide information about thyroid function because the amount of

data collected at inclusion in the ELFE cohort was already large. More specific studies on the

topic with thyroid hormone measurements are warranted.

Moreover, we did not have information on the time between diagnosis and pregnancy

that may induce different severity of thyroid diseases. Some of the asymptomatic women may


14

present undiagnosed antibody positivity without thyroid dysfunction, and some women

declaring pre-pregnancy hyperthyroidism may have fully recovered from the disease. In our

study, although our cohort was large, we could not separately evaluate the effects of pre-

pregnancy hyperthyroidism or thyroiditis on pregnancy outcome because of the limited

number of affected women. Another limitation was that we were unable to study some

outcomes (hypertension, prematurity) because of too few cases in the exposed group. We did

not have information on treatment of thyroid disease during pregnancy and whether fetal

outcomes differ between women with adequate and non-adequate treated disease. However,

our results represent the overall effect and indicate that the average situation in France may

not be optimal. Finally, only live births (≥ 33 amenorrhea weeks) were included in the ELFE

cohort. If pre-pregnancy thyroid diseases affect the probability of miscarriage or extreme

prematurity, our results could be biased, probably by underestimating the effect of thyroid

diseases.

Few epidemiologic studies have evaluated the risk of complications during pregnancy

related specifically to thyroid diseases before conception. Our observations reflect the

complexity of thyroid function and dysfunction on fertility and pregnancy outcome in women

with pre-existing thyroid diseases. Particular care is required in the management of these

women. Knowledge about the consequences of thyroid dysfunction should be optimized by

educational strategies to improve medical care and compliance with treatment. Normal

thyroid function during pre-conceptional phase and throughout pregnancy should be a key

objective for the prevention of pregnancy complications and prevention of morbidity in

fetuses and neonates. Moreover, in line with the developmental origins of health and disease

theory, pre-pregnancy thyroid pathologies may be among the early conditions that could have

long-term consequences on cognitive development 39

. Optimal maternal thyroid function is

necessary for offspring development, and further studies are needed to assess


15

neurodevelopment outcomes of children of women with pre-pregnancy thyroid diseases and

to understand the underlying mechanisms 40,41

.

Conclusion

In our study, pre-pregnancy thyroid diseases were associated with risk of infertility treatment,

gestational diabetes, and premature rupture of membranes. The association between history of

hypothyroidism due to a disease or as a potential side effect of surgical or cancer treatment

and moderate adverse effects on fetal head circumference growth needs replication with a

larger number of participants.

Acknowledgments

The ELFE survey is a joint project between the French Institute for Demographic Studies

(INED) and the National Institute of Health and Medical Research (INSERM), in partnership

with the French blood transfusion service (Etablissement français du sang, EFS), Santé

publique France, the National Institute for Statistics and Economic Studies (INSEE), the

Direction générale de la santé (DGS, part of the Ministry of Health and Social Affairs), the

Direction générale de la prévention des risques (DGPR, Ministry for the Environment), the

Direction de la recherche, des études, de l’évaluation et des statistiques (DREES, Ministry of

Health and Social Affairs), the Département des études, de la prospective et des statistiques

(DEPS, Ministry of Culture), and the Caisse nationale des allocations familiales (CNAF), with

the support of the Ministry of Higher Education and Research and the Institut national de la

jeunesse et de l’éducation populaire (INJEP).

We thank the members of the ELFE Ined-Inserm-EFS joint unit and above all the families

involved in the ELFE cohort without whom this study would not have been possible.

Financial support


16

Marion Lecorguillé received a scholarship from the Open Health Institute for this work.

The ELFE study receives a government grant managed by the National Research Agency

under the “Investissements d’avenir” program (ANR 11 EQPX 0038).

Conflicts of Interest

The authors have nothing to disclose

Ethical Standards

The authors assert that all procedures contributing to this work have been approved by the

ethics committee of Créteil (CPP), the national committee on information concerning health

research (CCTIRS) and the Data Protection Authority (Commission Nationale de

l’Informatique et des Libertés, CNIL).

References

1. Springer D, Jiskra J, Limanova Z, Zima T, Potlukova E. Thyroid in pregnancy: From

physiology to screening. Crit Rev Clin Lab Sci. 2017;54(2),102-116.

doi:10.1080/10408363.2016.1269309

2. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Role of thyroid hormone

during early brain development. Eur J Endocrinol. 2004;151 Suppl 3,U25-37.

3. Korevaar TIM, Chaker L, Jaddoe VWV, Visser TJ, Medici M, Peeters RP. Maternal and

Birth Characteristics Are Determinants of Offspring Thyroid Function. J Clin

Endocrinol Metab. 2016;101(1),206-213. doi:10.1210/jc.2015-3559

4. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid

Association for the Diagnosis and Management of Thyroid Disease During Pregnancy

and the Postpartum. Thyroid. 2017;27(3),315-389. doi:10.1089/thy.2016.0457

5. Léger J, dos Santos S, Larroque B, Ecosse E. Pregnancy outcomes and relationship to

treatment adequacy in women treated early for congenital hypothyroidism: a

longitudinal population-based study. J Clin Endocrinol Metab. 2015;100(3),860-869.

doi:10.1210/jc.2014-3049

6. Dong A, Stagnaro-Green A. Differences in Diagnostic Criteria Mask the True

Prevalence of Thyroid Disease in Pregnancy - A Systematic Review and Meta-Analysis.

Thyroid Off J Am Thyroid Assoc. November 2018. doi:10.1089/thy.2018.0475


17

7. Korevaar TIM, Medici M, Visser TJ, Peeters RP. Thyroid disease in pregnancy: new

insights in diagnosis and clinical management. Nat Rev Endocrinol. 2017;13(10),610-

622. doi:10.1038/nrendo.2017.93

8. Casey BM, Dashe JS, Wells CE, et al. Subclinical Hypothyroidism and Pregnancy

Outcomes: Obstet Gynecol. 2005;105(2),239-245.

doi:10.1097/01.AOG.0000152345.99421.22

9. Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Thyroid dysfunction and

pregnancy outcomes. Iran J Reprod Med. 2015;13(7),387-396.

10. Teng W, Shan Z, Patil-Sisodia K, Cooper DS. Hypothyroidism in pregnancy. Lancet

Diabetes Endocrinol. 2013;1(3),228-237. doi:10.1016/S2213-8587(13)70109-8

11. Maraka S, Ospina NMS, O’Keeffe DT, et al. Subclinical Hypothyroidism in Pregnancy:

A Systematic Review and Meta-Analysis. Thyroid. 2016;26(4),580-590.

doi:10.1089/thy.2015.0418

12. Krassas GE. Thyroid disease and female reproduction. Fertil Steril. 2000;74(6),1063-

1070.

13. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal Thyroid

Hypofunction and Pregnancy Outcome: Obstet Gynecol. 2008;112(1),85-92.

doi:10.1097/AOG.0b013e3181788dd7

14. Männistö T, Mendola P, Grewal J, Xie Y, Chen Z, Laughon SK. Thyroid Diseases and

Adverse Pregnancy Outcomes in a Contemporary US Cohort. J Clin Endocrinol Metab.

2013;98(7),2725-2733. doi:10.1210/jc.2012-4233

15. Hou J, Yu P, Zhu H, et al. The impact of maternal hypothyroidism during pregnancy on

neonatal outcomes: a systematic review and meta-analysis. Gynecol Endocrinol.

2016;32(1),9-13. doi:10.3109/09513590.2015.1104296

16. De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet Diabetes

Endocrinol. 2018;6(7),575-586. doi:10.1016/S2213-8587(17)30402-3

17. Karakosta P, Alegakis D, Georgiou V, et al. Thyroid Dysfunction and Autoantibodies in

Early Pregnancy Are Associated with Increased Risk of Gestational Diabetes and

Adverse Birth Outcomes. J Clin Endocrinol Metab. 2012;97(12),4464-4472.

doi:10.1210/jc.2012-2540

18. Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol.

2013;1(3),238-249. doi:10.1016/S2213-8587(13)70086-X

19. Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J. Management of Graves’

hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and

caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol. 2009;160(1),1-8.

doi:10.1530/EJE-08-0663

20. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al. Effect of maternal

hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin

Endocrinol (Oxf). 2001;54(3),365-370.


18

21. van den Boogaard E, Vissenberg R, Land JA, et al. Significance of (sub)clinical thyroid

dysfunction and thyroid autoimmunity before conception and in early pregnancy: a

systematic review. Hum Reprod Update. 2011;17(5),605-619.

doi:10.1093/humupd/dmr024

22. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association

between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of

evidence. BMJ. 2011;342(may09 1),d2616-d2616. doi:10.1136/bmj.d2616

23. Hirsch D, Levy S, Nadler V, Kopel V, Shainberg B, Toledano Y. Pregnancy outcomes in

women with severe hypothyroidism. Eur J Endocrinol. 2013;169(3),313-320.

doi:10.1530/EJE-13-0228

24. Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions for clinical

and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane

Database Syst Rev. 2013;(5),CD007752. doi:10.1002/14651858.CD007752.pub3

25. Earl R, Crowther CA, Middleton P. Interventions for hyperthyroidism pre-pregnancy

and during pregnancy. Cochrane Database Syst Rev. 2013;(11),CD008633.

doi:10.1002/14651858.CD008633.pub3

26. Charles MA, Thierry X, Lanoe J-L, et al. Cohort Profile: The French National cohort of

children ELFE: birth to 5 years. Int J Epidemiol. November 2019.

doi:10.1093/ije/dyz227

27. Ego A, Prunet C, Blondel B, Kaminski M, Goffinet F, Zeitlin J. [Customized and non-

customized French intrauterine growth curves. II - Comparison with existing curves and

benefits of customization]. J Gynecol Obstet Biol Reprod (Paris). 2016;45(2),165-176.

doi:10.1016/j.jgyn.2015.08.008

28. Léger J, Ecosse E, Roussey M, Lanoë JL, Larroque B, French Congenital

Hypothyroidism Study Group. Subtle health impairment and socioeducational attainment

in young adult patients with congenital hypothyroidism diagnosed by neonatal

screening: a longitudinal population-based cohort study. J Clin Endocrinol Metab.

2011;96(6),1771-1782. doi:10.1210/jc.2010-2315

29. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long

term adverse consequences for mother and child. BMJ. 2017;356:j1. doi:10.1136/bmj.j1

30. Iwen KA, Schröder E, Brabant G. Thyroid Hormones and the Metabolic Syndrome. Eur

Thyroid J. 2013;2(2),83-92. doi:10.1159/000351249

31. Chen L-M, Du W-J, Dai J, et al. Effects of Subclinical Hypothyroidism on Maternal and

Perinatal Outcomes during Pregnancy: A Single-Center Cohort Study of a Chinese

Population. Gao C-Q, ed. PLoS ONE. 2014;9(10),e109364.

doi:10.1371/journal.pone.0109364

32. Blazer S, Moreh-Waterman Y, Miller-Lotan R, Tamir A, Hochberg Z. Maternal

hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet Gynecol.

2003;102(2),232-241.


19

33. Su P-Y, Huang K, Hao J-H, et al. Maternal thyroid function in the first twenty weeks of

pregnancy and subsequent fetal and infant development: a prospective population-based

cohort study in China. J Clin Endocrinol Metab. 2011;96(10),3234-3241.

doi:10.1210/jc.2011-0274

34. Männistö T, Vääräsmäki M, Pouta A, et al. Perinatal outcome of children born to

mothers with thyroid dysfunction or antibodies: a prospective population-based cohort

study. J Clin Endocrinol Metab. 2009;94(3),772-779. doi:10.1210/jc.2008-1520

35. Korevaar TIM, Muetzel R, Medici M, et al. Association of maternal thyroid function

during early pregnancy with offspring IQ and brain morphology in childhood: a

population-based prospective cohort study. Lancet Diabetes Endocrinol. 2016;4(1),35-

43. doi:10.1016/S2213-8587(15)00327-7

36. Lundgren EM, Cnattingius S, Jonsson B, Tuvemo T. Intellectual and psychological

performance in males born small for gestational age with and without catch-up growth.

Pediatr Res. 2001;50(1),91-96. doi:10.1203/00006450-200107000-00017

37. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal Thyroid Function during

Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R

Study. J Clin Endocrinol Metab. 2010;95(9),4227-4234. doi:10.1210/jc.2010-0415

38. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal

hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year

follow-up study. Clin Endocrinol (Oxf). 2003;59(3),282-288.

39. Levie D, Korevaar TIM, Bath SC, et al. Association of Maternal Iodine Status With

Child IQ: A Meta-Analysis of Individual Participant Data. J Clin Endocrinol Metab.

2019;104(12),5957-5967. doi:10.1210/jc.2018-02559

40. Haddow JE. Maternal Thyroxine and Fetal Brain Development: The Latest Chapter, a

Look Back, and Considerations for the Future. J Clin Endocrinol Metab.

2013;98(4),1388-1390. doi:10.1210/jc.2013-1646

41. Korevaar TIM, Tiemeier H, Peeters RP. Clinical associations of maternal thyroid

function with fetal brain development:Epidemiological interpretation and overview of

available evidence. Clin Endocrinol (Oxf). April 2018. doi:10.1111/cen.13724

Figure 1: Flow of the women in the study. Selection of women with pre-pregnancy thyroid

diseases.


20

Table 1: Characteristics of ELFE women with and without pre-pregnancy thyroid diseases.

Demographic data

N

No thyroid diseases

(N=16,122)

Pre-pregnancy

thyroid diseases

(N=273)

P-value

Maternal age (years) 16,387 30.6 ± 5.1 32.0 ± 5.0 <.001

Maternity unit level 16,395

Level 2 and 3 centers 76.9 (12393) 80.6 (220) 0.15

Place of birth (France) 16,297 87.2 (13970) 89.3 (242) 0.30

Maternal education 16,392

Tertiary education 59.9 (9648) 66.7 (182) 0.023

Living with a partner

(yes)

16,321 94.5 (15169) 96.7 (263) 0.12

Social health insurance

coverage

16,326

Related to precarious

situations

8.5 (1362) 7.0 (19) 0.39

Employment status 16,027 0.14

Employed, student 80.2 (12635) 83.4 (226)

Housewife, parental leave 11.7 (1847) 11.8 (32)

Other, unemployment 8.1 (1274) 4.8 (13)

Smoking during

pregnancy

16,300 20.5 (3286) 15.1 (41) 0.028

Pre-pregnancy BMI* 16,201 <.001

Underweight 7.9 (1263) 5.5 (15)

Normal weight 65.0 (10355) 54.6 (148)

Overweight 17.2 (2746) 20.3 (55)

Obese 9.8 (1566) 19.6 (53)

Primiparous 16,317 45.8 (7350) 43.4 (118) 0.43

Number of ultrasounds 15,926 0.01

≤ 5 76.7 (12018) 70.2(186)

>5 23.3 (3643) 29.8 (79)

Prenatal consultations 16,150 0.41

< 7 10.4 (1645) 9.7 (26)

7–9 68.4 (10859) 65.7 (176)

> 9 21.3 (3378) 24.6 (66)

Data are % (n) or mean ± SD.

*Body mass index (BMI) was classified according to the World Health Organisation as

underweight, <18.5 kg/m²; normal weight, 18.5 to <25 kg/m²; overweight, 25.0 to <30 kg/m²;

obesity, ≥30 kg/m².


21

Table 2: Multivariable analysis of pregnancy and birth outcomes for women with and without

pre-pregnancy thyroid diseases before and after adjustment for confounding factors and pre-

pregnancy BMI.

Outcomes* Unadjusted model Adjusted model 1 Adjusted model 2

Categorical variables OR [95% CI] OR [95% CI] OR [95% CI]

Infertility treatment 1.74 [1.19,2.55]ª 1.57 [1.07,2.31]b 1.55 [1.05,2.28]

b

Gestational diabetes 1.68 [1.15,2.44]ª 1.58 [1.08,2.30]b 1.27 [0.86,1.88]

Hospitalization during

pregnancy 1.28 [0.94,1.74] 1.34 [0.99,1.83] 1.31 [0.96,1.79]

Induction of labor

Spontaneous labor 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)

Induction 1.10 [0.81,1.49] 1.09 [0.80,1.48] 1.01 [0.74,1.37]

Prelabor caesarean section 1.34 [0.90,1.97] 1.23 [0.83,1.82] 1.10 [0.74,1.64]

Mode of birth

Vaginal delivery 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)

Assisted delivery** 1.05 [0.73,1.51] 1.06 [0.73,1.56] 1.07 [0.73,1.57]

Caesarean section 1.22 [0.90,1.65] 1.14 [0.84,1.56] 1.02 [0.74,1.40]

Premature rupture of

membranes 1.28 [0.89,1.85] 1.27 [0.87,1.85] 1.27 [0.87,1.85]

Birth weight categories***

AGA 1.00 (Reference) 1.00 (Reference) NA

SGA 0.82 [0.52,1.29] 0.86 [0.54,1.35] LGA 1.03 [0.69,1.54] 1.03 [0.69,1.53] Quantitative variables β [95% CI] β [95% CI] β [95% CI]

Gestational age

(amenorrhea weeks) 0.03 [-0.14,0.20] 0.02 [-0.15,0.19] 0.01 [-0.16,0.18]

Birth weight (g) 41.25 [-15.95,98.45] 29.06 [-18.86,76.98] 8.29 [-39.25,55.82]

Birth length (cm) 0.27 [0.002,0.54]b 0.19 [-0.04,0.42] 0.15 [-0.08,0.38]

Head circumference (cm) -0.005 [-0.18,0.17] -0.04 [-0.20,0.13] -0.08 [-0.24,0.08]

Data are odds ratios (ORs) or beta (β) values and 95% confidence intervals (CIs).

Model 1: adjusted for maternal education level, maternal age, parity, smoking during

pregnancy and infant sex and gestational age for head circumference, birth weight and birth

length. Model 2: model 1 and adjustment for BMI as a continuous variable.

* Maximal N for outcome in unadjusted model (N=16,302) and minimal N in adjusted model

2 (N=14,507). When the sample was restricted to women included in the 3 models, results

were similar as above for all 3 models.

** Assisted delivery: forceps, spatulas, vacuum

*** A customized standard to assess fetal growth: SGA, small for gestational age (< 10th

percentile); AGA, appropriate for gestational age (10th

to 90th

percentile); LGA, large for

gestational age (>90th

percentile). (see methods)

ª p<.01 b p<.05. NA: not applicable (model already adjusted for BMI)


22

Table 3: Multivariable analysis of pregnancy and birth outcomes for women with pre-

pregnancy thyroid diseases and without pre-pregnancy thyroid diseases after excluding

women with a history of other diseases from the two groups.

Outcomes* No. cases¹

(%)

Unadjusted model Adjusted model 1 Adjusted model 2

Categorical

variables OR [95% CI] OR [95% CI] OR [95% CI]

Infertility treatment 19 (9.3) 1.39 [0.86,2.24] 1.28 [0.79,2.07] 1.26 [0.77,2.04]

Gestational diabetes 16 (7.8) 1.60 [0.96,2.68] 1.56 [0.93,2.62] 1.35 [0.80,2.29]

Hospitalization

during pregnancy

37 (17.6) 1.31 [0.91,1.87] 1.39 [0.97,1.99] 1.37 [0.96,1.97]

Induction of labor


Induction 43 (20.5) 1.16 [0.82,1.63] 1.17 [0.83,1.65] 1.10 [0.78,1.56]

Prelabor caesarean

section

18 (8.6) 1.15 [0.70,1.88] 1.08 [0.66,1.78] 1.00 [0.61,1.65]

Mode of birth


Assisted delivery** 30 (14.3) 1.10 [0.74,1.64] 1.14 [0.75,1.73] 1.14 [0.75,1.74]

Caesarean section 36 (17.1) 1.07 [0.74,1.55] 1.03 [0.70,1.49] 0.95 [0.65,1.39]

Premature rupture

of membranes

30 (14.5) 1.52 [1.03,2.25]ª 1.51 [1.01,2.26]ª 1.51 [1.01,2.25]ª

Birth weight

categories***


SGA 15 (7.1) 0.78 [0.46,1.33] 0.82 [0.48,1.40] LGA 21 (10.0) 0.99 [0.63,1.58] 0.99 [0.63,1.56] Quantitative

variables β [95% CI] β [95% CI] β [95% CI]

Gestational age

(amenorrhea weeks)

0.07 [-0.11,0.26] 0.07 [-0.12,0.26] 0.05 [-0.14,0.24]

Birth weight (g) 45.17 [-19.19,109.5] 21.88[-31.95,75.71] 7.02 [-46.33,60.37]

Birth length (cm) 0.39 [0.09,0.70]ª 0.28 [0.02,0.54]ª 0.23 [,0.03,0.49]

Head circumference

(cm)

-0.02 [-0.22,0.19] -0.06 [-0.25,0.12] -0.10 [-0.28,0.08]

¹N: number of cases in pre-pregnancy thyroid group after excluding other pathologies before

adjustment.

Model 1: adjusted on maternal education level, maternal age, parity, smoking during pregnancy

and infant sex and gestational age for head circumference, birth weight and birth length.

Model 2: model 1 and additional adjustment for BMI as a continuous variable.

* Maximal N for outcome in unadjusted model (N=14,258) and minimal N in adjusted model 2

(N=12,701). When the sample was restricted to women included in the 3 models, results were

similar as above for all 3 models.

** Assisted delivery: forceps, spatulas, vacuum


23

*** Customized standard to assess fetal growth: SGA, small for gestational age (< 10th


to 90th



percentile). (see methods).

ªp<.05. NA: not applicable because the model is already adjusted for BMI


24

Table 4: Comparison of outcomes for women without pre-pregnancy thyroid diseases and

with pre-pregnancy hypothyroidism§ (hyperthyroidism or unspecified thyroid diseases

excluded)

Fertility and

pregnancy

complications

N No pre-

pregnancy

thyroid diseases

(N=16,122)

Pre-pregnancy

hypothyroidism

(N=196)

P-

value

Adjusted model 2

Infertility treatment 16,155 7.0 (1124) 12.0 (23) 0.007 1.55 [0.99,2.43]

Gestational diabetes 15,752 7.5 (1165) 12.4 (24) 0.010 1.24 [0.78,1.95]

Gestational age at

birth (amenorrhea

weeks)

16,225 39.6 ± 1.4 39.6 ± 1.3 0.87 -0.04 [-0.24,0.16]


pregnancy

16,225 15.3 (2455) 16.3 (32) 0.70 1.10 [0.75,1.61]

Induction of labor 16,201 0.31

Spontaneous labor 72.1 (11535) 69.4 (136) 1.00 (Reference)

Induction 19.3 (3084) 18.9 (37) 0.90 [0.62,1.30]

Prelabor caesarean

section

8.7 (1386) 11.7 (23) 1.11 [0.70,1.75]

Mode of delivery 16,078 0.21

Vaginal delivery 69.7 (11073) 64.6 (126) 1.00 (Reference)

Assisted delivery* 12.9 (2041) 13.3 (26) 1.11 [0.71,1.72]

Caesarean section 17.4 (2769) 22.1 (43) 1.12 [0.78,1.60]


membranes

15,991 9.8 (1553) 14.5 (28) 0.030 1.49 [0.99,2.27]

Birth weight (g) 16,121 3334.8 ± 478.4 3366.8 ± 467.8 0.35 -0.20 [-55.9,55.5]

Birth length (cm) 14,897 49.6 ± 2.1 49.8 ± 2.1 0.34 0.02 [-0.25,0.29]

Head circumference

(cm)

14,806 34.4 ± 1.4 34.3 ± 1.4 0.34 -0.20 [-0.39,-0.01]

Birth weight

categories**

15,851 0.86

SGA 9.3 (1459) 8.2 (16) NA

AGA 80.8 (12646) 81.5 (159)

LGA 9.9 (1551) 10.3 (20)

§ pre-pregnancy hypothyroidism due to a disease or as a potential side effect of treatment

(Hashimoto’s disease, hypothyroidism unspecified, no thyroid, thyroidectomy, thyroid cancer)

Model 2: adjusted on maternal education level, maternal age, parity, smoking during pregnancy,

BMI and infant sex and gestational age for head circumference, birth weight and birth length.

* Assisted delivery: forceps, spatulas, vacuum

** A customized standard to assess fetal growth: SGA, small for gestational age (< 10th


to 90th



percentile) (see methods)


25

Table 5: Multivariable analysis of pregnancy and birth outcomes for women with pre-

pregnancy hypothyroidism§ but no other diseases compared to women without pre-pregnancy

thyroid nor other diseases

Outcomes* No.

cases¹

(%)

No adjustment Adjusted model

1

Adjusted model 2

Qualitative variables OR [95% CI] OR [95% CI] OR [95% CI]

Infertility treatment 16 (11.0) 1.68 [1.00,2.84] 1.52 [0.89,2.58] 1.49 [0.87,2.53]

Gestational diabetes 11 (7.5) 1.54 [0.83,2.86] 1.51 [0.81,2.81] 1.24 [0.66,2.34]

Hospitalization

during pregnancy

22 (14.8) 1.06 [0.67,1.67] 1.13 [0.72,1.79]

1.11 [0.70,1.75]

Induction of labor


Induction 28 (18.8) 1.04 [0.69,1.58] 1.05 [0.69,1.60] 0.96 [0.63,1.47]

Prelabor caesarean

section

13 (8.7) 1.14 [0.64,2.04] 1.09 [0.61,1.95] 0.96 [0.53,1.73]

Mode of birth


Assisted delivery** 24 (16.1) 1.28 [0.82,2.01] 1.33 [0.83,2.14] 1.31 [0.82,2.11]

Caesarean section 26 (17.4) 1.13 [0.73,1.74] 1.11 [0.72,1.73] 0.99 [0.64,1.55]

Premature rupture

of membranes

25 (17.1) 1.86 [1.20,2.86]ª 1.82 [1.16,2.84]ª 1.79 [1.14,2.80]b

Birth weight

categories***


SGA 11 (7.4) 0.8 [0.43,1.49] 0.83 [0.45,1.55] LGA 14 (9.4) 0.93 [0.53,1.62] 0.93 [0.53,1.62] Quantitative

variables β [95% CI] β [95% CI] β [95% CI]

Gestational age

(amenorrhea weeks)

0.03 [-0.19,0.25] 0.03 [-0.20,0.25] 0.004 [-0.22,0.23]

Birth weight (g) 29.54

[-46.89,105.97]

14.42[-49.37,78.22] -8.53 [-71.62,54.57]

Birth length (cm) 0.31 [-0.04,0.67] 0.23 [-0.08,0.53] 0.16 [-0.14,0.47]

Head circumference

(cm)

-0.12 [-0.36,0.11] -0.17[-0.39,0.04] -0.23 [-0.44,-0.01]b

§ pre-pregnancy hypothyroidism due to a disease or as a potential side effect of treatment

(Hashimoto’s disease, hypothyroidism unspecified, no thyroid, thyroidectomy, thyroid cancer)

¹N: number of cases in pre-pregnancy hypothyroidism diseases group before adjustment

Model 1: adjusted on maternal education level, maternal age, parity, smoking during pregnancy

and infant sex and gestational age for head circumference, birth weight and birth length.

Model 2: model 1 and additional adjustment for BMI as a continuous variable

* Maximal N for outcome in unadjusted model (N=14,197) and minimal N in adjusted model2

(N=12,646). When the sample was restricted to subjects included in the 3 models, results were

similar as above for all 3 models.

**Forceps, spatulas, vacuum


26

*** Customized standard to assess fetal growth: SGA, small for gestational age (< 10th


to 90th



percentile). (see methods)

ª p<0.01 b p<0.05. NA: not applicable because the model is already adjusted for BMI.


27

Supplementary Table S1: Outcomes for women with and without pre-pregnancy thyroid

diseases.

Fertility and pregnancy

complications

N No pre-pregnancy

thyroid diseases

(N=16,122)

Pre-pregnancy

thyroid diseases

(N=273)

P-value

Infertility treatment 16,230 7.0 (1124) 11.7 (31) 0.004

Gestational diabetes 15,826 7.5 (1165) 11.9 (32) 0.006

Gestational age at birth

(amenorrhea weeks) 16,302 39.6 ± 1.4 39.7 ± 1.3 0.73


pregnancy 16,301 15.3 (2455) 18.8 (51) 0.12

Induction of labor 16,277 0.32

Spontaneous labor 72.1 (11535) 68.8 (187)

Induction

19.3 (3084) 20.2 (55)

Pre-labor caesarean section

8.7 (1386) 11.0 (30)

Mode of delivery 16,154 0.45

Vaginal delivery 69.7 (11073) 66.8 (181)

Assisted delivery*

12.9 (2041) 12.9 (35)

Caesarean section

17.4 (2769) 20.3 (55)


membranes 16,067 9.8 (1553) 12.3 (33) 0.18

Birth weight (g) 16,198 3334.8 ± 478.4 3376 ± 460.3 0.16

Birth length (cm) 14,967 49.6 ± 2.1 49.9 ± 2.0 0.05

Head circumference (cm) 14,875 34.4 ± 1.4 34.4 ± 1.4 0.96

Birth weight categories** 15,926 0.68

SGA 9.3 (1459) 7.8 (21)

AGA

80.8 (12646) 81.9 (221)

LGA

9.9 (1551) 10.4 (28)

Data are % (n) or mean ± SD.

* Assisted delivery: forceps, spatulas, and vacuum

**A customized standard to assess fetal growth: SGA, small for gestational age (< 10th


to 90th



percentile (see methods))

pregnancy outcomes in women with pre-existing thyroid

Documents